Articles

146 www.thelancet.com Vol 383 January 11, 2014

Eects of vitamin D supplements on bone mineral density:
a systematic review and meta-analysis
Ian R Reid, Mark J Bolland, Andrew Grey
Summary
Background Findings from recent meta-analyses of vitamin D supplementation without co-administration of calcium
have not shown fracture prevention, possibly because of insu cient power or inappropriate doses, or because the
intervention was not targeted to decient populations. Despite these data, almost half of older adults (older than
50 years) continue to use these supplements. Bone mineral density can be used to detect biologically signicant
eects in much smaller cohorts. We investigated whether vitamin D supplementation aects bone mineral density.
Methods We searched Web of Science, Embase, and the Cochrane Database, from inception to July 8, 2012, for trials
assessing the eects of vitamin D (D3 or D2, but not vitamin D metabolites) on bone mineral density. We included all
randomised trials comparing interventions that diered only in vitamin D content, and which included adults
(average age >20 years) without other metabolic bone diseases. We pooled data with a random eects meta-analysis
with weighted mean dierences and 95% CIs reported. To assess heterogeneity in results of individual studies, we
used Cochrans Q statistic and the I statistic. The primary endpoint was the percentage change in bone mineral
density from baseline.
Findings Of 3930 citations identied by the search strategy, 23 studies (mean duration 235 months, comprising
4082 participants, 92% women, average age 59 years) met the inclusion criteria. 19 studies had mainly white
populations. Mean baseline serum 25-hydroxyvitamin D concentration was less than 50 nmol/L in eight studies
(n=1791). In ten studies (n=2294), individuals were given vitamin D doses less than 800 IU per day. Bone mineral
density was measured at one to ve sites (lumbar spine, femoral neck, total hip, trochanter, total body, or forearm) in
each study, so 70 tests of statistical signicance were done across the studies. There were six ndings of signicant
benet, two of signicant detriment, and the rest were non-signicant. Only one study showed benet at more than
one site. Results of our meta-analysis showed a small benet at the femoral neck (weighted mean dierence 08%,
95% CI 0214) with heterogeneity among trials (I=67%, p<000027). No eect at any other site was reported,
including the total hip. We recorded a bias toward positive results at the femoral neck and total hip.
Interpretation Continuing widespread use of vitamin D for osteoporosis prevention in community-dwelling adults
without specic risk factors for vitamin D deciency seems to be inappropriate.
Funding Health Research Council of New Zealand.
Introduction
Vitamin D, like calcium, has long been regarded as a
fundamental part of the prevention and treatment of
osteoporosis. Low vitamin D concentrations result in
secondary hyperparathyroidism and accelerated bone
loss, although the development of secondary hyper-
para thyroidism varies, even in patients with severe
vitamin D deciency.
1,2
Findings from observational
studies show inconsistent associations between bone
mineral density and vitamin D status,
3,4
and debate
continues regarding optimum concentrations of
25-hydroxyvitamin D for the best possible skeletal
health.
5,6
However, results from meta-analyses of trials
of vitamin D alone (ie, not with calcium) failed to show
an association between supple mentation and fracture
prevention.
7,8
This nding could be attributable to
aspects of the study design (eg, study power, the
population recruited, or the vitamin D dose used).
Alternatively, vitamin D might not have a protective
eect on bone, as has been postulated.
7
Therefore,
surrogate endpoints such as bone mineral density,
which can be used to detect biologically signicant
eects in small cohorts, should be examined closer.
Furthermore, some studies might have used inadequate
doses of vitamin D or a baseline vitamin D status of the
populations studied that was not low enough for the
intervention to produce a signicant eect. Thus, the
study of the eect of vitamin D supplementation on bone
density in terms of the dose given and baseline vitamin D
status are important questions that can be addressed in
the many studies assessing bone mineral density. Con-
cerns about the cardiovascular safety of calcium plus
vitamin D supplements
9
warrant the investigation of
vitamin D as a monotherapy.
We aimed to address these questions by system -
atically reviewing all randomised, controlled trials of
cholecalciferol or ergocalciferol that have included bone
mineral density data, irrespective of whether this was
the primary endpoint of the study, in populations
without other disorders likely to aect bone and
Lancet 2014; 383: 14655
Published Online
October 11, 2013
http://dx.doi.org/10.1016/
S0140-6736(13)61647-5
See Comment page 108
Department of Medicine,
Faculty of Medical and Health
Sciences, University of
Auckland, Auckland, New
Zealand (Prof I R Reid MD,
M J Bolland PhD, A Grey MD);
and Department of
Endocrinology, Auckland
District Health Board,
Auckland, New Zealand
(I R Reid, A Grey)
Correspondence to:
Prof Ian R Reid, Faculty of
Medical and Health Sciences,
University of Auckland,
Private Bag 92019, Auckland,
New Zealand
i.reid@auckland.ac.nz
Articles
www.thelancet.com Vol 383 January 11, 2014 147
calcium metabol ism. Despite the negative ndings
from fracture studies, almost half of adults in the USA
use vitamin D supplements.
10
There fore, to ensure
appro priate targeting of this common intervention,
investi gators need to establish in which groups the
vitamin improves bone health.
Methods
Search strategy and selection criteria
We did a systematic review and meta-analysis in accor-
dance with the PRISMA (Preferred Reporting Items for
Systematic reviews and meta-Analyses) guide lines, and
used a predetermined protocol. To qualify for inclusion,
Trial
duration
(months)
N Mean age
(range;
years)
Country Sex (%
female)
Mean 25OHD
(SD or range; nmol/L)
Dietary
calcium
(mg/day)
Weight
(kg)
Intervention Co-
interventions*
Comorbidities
Baseline On
vitamin D
Christiansen,
1980
18
24 149 50
(inclusion
criteria
4554)
Denmark 100 .. .. .. .. Vitamin D3 2000 IU/day
vs placebo
Calcium
500 mg/day
..
Dawson-
Hughes, 1991
19
12 276 62 USA (white) 100 71 95 390 68 Vitamin D3 400 IU/day
vs placebo
Calcium
380 mg/day
..
Dawson-
Hughes, 1995
20
24 261 64 USA (white) 100 66 25 100 450 68 Vitamin D3 100 IU/day
vs 700 IU/day
Calcium
500 mg/day
..
Ooms,
1995
21
24 348 80
(inclusion
criteria
>70)
Holland 100 26 (1937) 62|| About
1120
71 Vitamin D3 400 IU/day
vs placebo
.. ..
Tuppurainen,**
1998
22
48 45 55
(inclusion
criteria
5059)
Finland 100 .. .. 730 61 Vitamin D3 300 IU/day
for 9 of 12 months per
year vs control
Hormone
treatment
..
Komulainen,**
1999 HRT
23
60 231 53 Finland 100 27 (10) .. 830 70 Vitamin D3
300 IU/ day for 9 of
12 months per year vs
placebo
Hormone
treatment
..
Komulainen, **
1999 no HRT
23
60 227 53 Finland 100 28 (11) .. 840 69 Vitamin D3:
300 IU/day for 9 of
12 months per year vs
placebo
Calcium
93 mg/day
..
Hunter,
2000
24
24 158 59 (4770) UK 100 71 (29) 104|| 1055 63 Vitamin D3 800 IU/day
vs placebo
.. ..
Patel,
2001
25

12 70 47 (2370) UK 100 72 (30119) +25 570 68 Vitamin D3 800 IU/day
vs placebo
.. ..
Venkatachalam,
2003
26
24 50 54 UK 68 .. .. .. .. Intramuscularvitamin D
300 000 IU/year vs
placebo
.. Treated
coeliac disease
Cooper,
2003
27
24 187 56 Australia 100 82 26 81 780 67 Vitamin D2:
10 000 IU/week vs
placebo
Calcium 1 g/day ..
Harwood,**
2004
28
12 75 80 (6792) UK 100 29 (1067) 40|| .. BMI
24 kg/m
Intramuscularvitamin
D2 300 000 IU vs no
treatment
No placebo or
calcium
..
Aloia,
2005
29
36 208 61 (5075) USA (100%
AA)
100 46 (19;
10100)
87|| 760 79 Vitamin D3 800 IU/day
for 2 years then
2000 IU/ day vs placebo
Calcium, to
1215 g/day
total intake
..
Zhu,*
2008
30
60 79 75
(inclusion
criteria
7080)
Australia 100 68 (26) 106|| 990 70 Vitamin D2 1000 IU/day
vs placebo
Calcium
12 g/day
..
Zhu,
2008
31
12 302 77 Australia 100 44 13 60 1100 73 Vitamin D2 1000 IU/day
vs placebo
Calcium 1 g/day ..
Andersen,
2008
32
12 173 37 Pakistanis
in Denmark
51 16
(IQR 1122)
45|| 530 73 Vitamin D3 400 IU/day
vs 800 IU/day vs placebo
.. ..
Viljakainen,
2009
33
6 54 29 (2149) Finland 0 62 15 82|| 1340 79 Vitamin D3 400 IU/day
vs 800 IU/day vs placebo
.. ..
(Continues on next page)
Articles
148 www.thelancet.com Vol 383 January 11, 2014
studies had to be randomised controlled trials com-
paring interventions that diered only in vitamin D
content, which were done in adults (average age
>20 years). The intervention could be a preparation of
vitamin D3 or D2, but not a vitamin D metabolite. If
other interventions were given (eg, calcium), they had
to be the same in all groups. Studies of individuals with
other disorders likely to aect bone and calcium
metabolism (eg, chronic kidney disease, pregnancy,
glucocorticoid use, and anti-epileptic drug use) were
not eligible. Data for bone mineral density (or in the
case of forearm assessment, bone mineral content) had
to be available, irrespective of whether this was the
primary endpoint. There were no language restrictions
on trial eligibility.
We searched Web of Science, Embase, and the
Cochrane Database from inception to July 8, 2012, with
the terms vitamin D, or c(h)olecalciferol, or ergo-
calciferol, together with either randomised study,
randomised trial, or con trolled clinical trial. Addition-
ally, the reference lists of reviews of vitamin D were
screened for qualifying studies.
5,1116
Two authors (IRR,
MJB) independently conrmed the eligibility of studies
and collated the data from the qualifying studies. IRR
extracted the data which were double checked by MJB
and discrepancies resolved through discussion. Study
quality was assessed as recommended in the Cochrane
Handbook.
17
The com plete search strategy is available in
the appendix.
Statistical analysis
The primary endpoint was the percentage change in bone
mineral density from baseline. We pooled data with a
random eects meta-analysis with weighted mean dier-
ences and 95% CIs reported. To assess heterogeneity in
results of individual studies, we used Cochrans Q statistic
and the I statistic (I >50% was used as a threshold indi-
cating signicant heterogeneity). Publication bias was
assessed with Funnel plots and Eggers regression model.
The eects of vitamin D on bone mineral density were
compared between subgroups of trials dened by pre-
specied characteristics (eg, baseline age, vitamin D status,
treatment dose, and trial duration). All tests were two-
tailed and a p value of less than 005 was deemed statis-
tically signicant. We analysed data with Compre hensive
Meta-Analysis (version 2).
See Online for appendix
Trial
duration
(months)
N Mean age
(range;
years)
Country Sex (%
female)
Mean 25OHD
(SD or range; nmol/L)
Dietary
calcium
(mg/day)
Weight
(kg)
Intervention Co-
interventions*
Comorbidities
Baseline On
vitamin D
(Continued from previous page)
Islam,
2010
34
12 100 22 Bangladesh 100 36 (107) 68|| .. 49 Vitamin D3 400 IU/day
vs placebo
.. ..
Jorde,
2010
35
12 421 47 (2170) Norway 63 58 21 141|| .. BMI
35 kg/m
Vitamin D3
40 000 IU/week vs
20 000 IU/week vs
placebo
Calcium
500 mg/day
Overweight
Verschueren,
2011
36
6 113 80
(inclusion
criteria
>70)
Belgium 100 53 (34) 146|| .. 67 Vitamin D3 880 IU/day
vs 1600 IU/day
Vibration,
factorial design
..
Grimnes,
2012
37
12 297 63
(inclusion
criteria
5080)
Norway 100 71 (23) 185|| 820 BMI
25 kg/m
Vitamin D3 800 IU/day
vs 6500 IU/day
Calcium 1 g/day ..
Rastelli,
2011
38
6 60 62 USA
(13% AA)
100 56 12 74 .. BMI
32 kg/m
Vitamin D2
50 000 IU/week vs per
month vs placebo
Calcium
1 g/day, vitamin
D3 400 IU/day
Anastrozole
Steensen,
2011
39
22 71 40 (2150) Norway 71 56 (25;
18143)
123|| .. BMI
26 kg/m
Vitamin D3
20 000/week vs placebo
Calcium
05 g/day
Multiple
sclerosis
Nieves,
2012
40
24 127 62 USA
(100% AA)
100 29 (13) 55|| 1000|||| 82 Vitamin D3 1000 IU/day
vs placebo
Calcium to
1 g/day total
intake
..
Age and 25OHD were assessed at baseline, unless shown otherwise. Komulainen and colleagues
23
study included two cohorts, only one of which received hormone treatment, so these studies are presented
separately; therefore, 24 cohorts are shown in the table. N=Number of participants randomly assigned. HRT=hormone replacement therapy. AA=AfricanAmerican. 25OHD=25-hydroxyvitamin D. *Given to both
groups. Compliance reported. Measured during study in group on low dose of vitamin D or placebo.25OHD concentrations were signicantly higher during the study than in the control group. Median IQR.
Other values for age, 25OHD, calcium intake, and weight are mean. ||25OHD concentrations signicantly increased during the study in the vitamin D group.**Unblinded study. 100 IU/day in year 5. 12
month intervention in a crossover study, crossover study starting in late s ummer. This is the treatment eect derived with multivariate regression analysis. 1 year after injection of vitamin D. Entry criteria
for study; other values are actual age ranges. ||||Including supplements.
Table 1: Characteristics of randomised controlled trials assessing the eects of vitamin D on bone mineral density in adults
Articles
www.thelancet.com Vol 383 January 11, 2014 149
3 2 1 0 1 2 3
3 2 1 0 1 2 3 4
Dawson-Hughes, 1991
19
Dawson-Hughes, 1995
20
Tuppurainen, 1998
22
Komulainen, 1999*
41
Komulainen, 1999
41
Hunter, 2000
24
Patel, 2001
25
Cooper, 2003
27
Harwood, 2004
28
Aloia, 2005
29
Andersen, 2008
32
Islam, 2010
34
Jorde 2010
35
Grimnes, 2011
37
Rastelli, 2011
38
Steensen, 2011
39
Nieves, 2012
40
Total
Test for heterogeneity:
I
2
=0%, p=06
07 (00 to 14)
02 (10 to 06)
09 (29 to 47)
07 (09 to 23)
01 (14 to 12)
01 (19 to 17)
06 (13 to 02)
02 (17 to 14)
14 (33 to 05)
01 (05 to 04)
06 (06 to 19)
17 (05 to 39)
01 (07 to 08)
01 (08 to 07)
05 (17 to 27)
02 (17 to 13)
01 (08 to 11)
00 (02 to 03)

12
9
04
2
3
2
10
2
2
23
3
1
10
10
1
2
6
p=08
10
7
2
8
8
7
8
8
5
8
12
5
11
p=0005
Weighted mean dierence in
lumbar spine BMD (%) (95% CI)
Weight
(%)
Weighted mean dierence in
femoral neck BMD (%) (95% CI)
Weight
(%)
A B
Dawson-Hughes, 1995
20
Ooms, 1995
21
Tuppurainen, 1998
22
Komulainen, 1999*
41
Komulainen, 1999
41
Hunter, 2000
24
Patel, 2001
25
Cooper, 2003
27
Harwood, 2004
28
Islam, 2010
34
Grimnes, 2011
37
Rastelli, 2011
38
Nieves, 2012
40
Total
Test for heterogeneity:
I
2
=67%, p=000027
15 (05 to 25)
19 (04 to 34)
37 (01 to 75)
01 (12 to 14)
00 (13 to 13)
05 (11 to 21)
06 (06 to 19)
07 (20 to 07)
11 (11 to 32)
28 (15 to 41)
01 (06 to 03)
18 (01 to 38)
06 (01 to 13)
08 (02 to 14)
3 2 1 0 1 2 3
Weighted mean dierence in
forearm BMD (%) (95% CI)
Weight
(%)
E
Christiansen, 1980
18
Ooms, 1995
21
Hunter, 2000
24
Cooper, 2003
27
Aloia, 2005
29
Steensen, 2011
39
Total
Test for heterogeneity:
I
2
=0%, p=08
4
1
11
8
75
2
p=009
12 (31 to 07)
03 (49 to 43)
07 (18 to 04)
03 (16 to 11)
03 (07 to 02)
10 (17 to 37)
03 (07 to 01)
Favours decreased
BMD with vitamin D
Favours increased
BMD with vitamin D
3 2 1 0 1 2 3
Ooms, 1995
21
Hunter, 2000
24
Patel, 2001
25
Cooper, 2003
27
Harwood, 2004
28
Aloia, 2005
29
Zhu, 2008
30
Zhu, 2008
31
Islam, 2010
34
Jorde 2010
35
Grimnes, 2011
37
Rastelli, 2011
38
Steensen, 2011
39
Verschueren 2011
36
Nieves, 2012
40
Total
Test for heterogeneity:
I
2
=39%, p=006
2
4
8
3
3
14
2
9
2
16
15
2
3
7
11
p=017
14
14
7
12
14
12
12
15
p=02
02 (19 to 15)
07 (05 to 19)
01 (08 to 06)
03 (10 to 16)
20 (05 to 35)
00 (04 to 04)
11 (09 to 32)
03 (04 to 10)
30 (12 to 48)
01 (03 to 04)
03 (06 to 01)
00 (19 to 18)
07 (06 to 20)
01 (09 to 08)
02 (04 to 07)
02 (01 to 04)
Weighted mean dierence in total
hip/trochanter BMD (%) (95% CI)
Weight
(%)
Weighted mean dierence in
total body BMD (%) (95% CI)
Weight
(%)
3 2 1 0 1 2 3
C D
Dawson-Hughes, 1991
19
Dawson-Hughes, 1995
20
Hunter, 2000
24
Patel, 2001
25
Aloia, 2005
29
Andersen, 2008
42
Zhu, 2008
31
Grimnes, 2011
37
Total
Test for heterogeneity:
I
2
=85%, p<001
01 (02 to 04)
02 (02 to 06)
02 (09 to 13)
06 (12 to 00)
01 (05 to 04)
20 (26 to 14)
00 (06 to 06)
00 (03 to 02)
03 (07 to 01)
Favours decreased
BMD with vitamin D
Favours increased
BMD with vitamin D
Figure 1: Meta-analysis of the
eects of vitamin D
supplementation on BMD at
ve skeletal sites
Weighted mean dierence in
(A) lumbar spine BMD,
(B) femoral neck BMD,
(C) total hip or trochanter
BMD, (D) total body BMD, or
(E) forearm BMD.
BMD=bone mineral density.
HRT=hormone replacement
therapy. *HRT. No HRT.
Articles
150 www.thelancet.com Vol 383 January 11, 2014
Role of the funding source
The sponsors of the study had no role in study design,
data collection, data analysis, data interpretation, or
writing of the report. IRR and MJB had full access to all
the data in the study and had nal responsibility for the
decision to submit for publication.
Results
Our search strategy identied 3930 unique publications,
the titles and abstracts of which were screened for
inclusion. The full text of 54 articles was retrieved, of
which 23 met the inclusion criteria (appendix). Reasons
for exclusion of the remaining articles were: intervention
not vitamin D (12), patients too young (two), study not
randomised (two), duplicate publication (ve), no data
for bone mineral density presented (six), and patients
had other major pathologies (four).
Table 1 shows descriptive data for the 23 qualifying
trials, and gure 1 shows the data for bone mineral density
data. One study (Komulainen and colleagues) included
two cohorts, one receiving and one not receiving hormone
treatment, which are presented separately, so 24 cohorts
are shown in the table. 18 studies were placebo-controlled,
two had open control groups
22,28
(but in one of these,
investigators assessing bone density assessment were
masked to treatment group
22
), and three were comparisons
between two dierent doses of vitamin D.
20,37,38
19 studies
were double-blind, and in one (presented in abstract
only)
26
blinding was not described. A rigorous method of
randomisation was explicitly described in 14 studies, and
allocation concealment in ten studies; in the remainder,
this information was absent or unclear. One study did not
provide details of participants who withdrew or were lost
to follow-up.
22
Participant completion rates ranged from
61% to 96%, and the weighted mean was 84%. Two
studies
30,38
seemed to have more non-completers in the
vitamin D group than in the control group, and one study
40

had more non-completers in the control group. Com-
pliance was more than 80% in the 14 studies in which it
was reported. Findings from two recent studies showed
bone mineral density at only one site,
30
and Eggers test
showed evidence of bias towards positive results at both
hip sites (gure 2), but not elsewhere (data not shown),
suggesting selective reporting.
The studies recruited 4082 participants, 92% women.
In six studies (n=871) the average age was younger than
50 years, and the weighted mean age for the 24 cohorts
was 59 years. 19 studies included mainly white popu-
lations, two were done exclusively in AfricanAmerican
individuals,
29,40
one took place in Bangladesh,
34
and
another studied Pakistani immigrants in Denmark.
32

Two studies included mainly overweight populations.
35,38

25-hydroxyvitamin D concentration was measured at
baseline in all individuals in 19 studies, in 15% in one
study,
23
and omitted in three.
18,22,26
A wide range of baseline
concentrations of 25-hydroxyvitamin D were reported.
The mean level was less than 30 nmol/L in ve studies
(n=1181), 3050 nmol/L in three studies (n=610),
5075 nmol/L in 11 studies (n=1860), and more than
75 nmol/L in only one study (187 healthy Australian
women in early postmenopause). In 12 studies, calcium
supplements were given to all trial groups. Two studies
(n=243) had average total calcium intakes of less than
750 mg per day.
25,32
One study
25
used a crossover design
whereas the others were all parallel group studies. Three
small studies were of 6 months duration, eight for 1 year,
and 12 for 25 years. The weighted mean trial duration
was 235 months.
Various supplement regimens were assessed. Most
trials used daily oral dosing, although in two studies,
supplementation was given only for 9 months of each
year. Four studies (n=739) dosed participants at weekly or
monthly intervals, and two studies (n=125) gave annual
intramuscular injections of 300 000 units. When doses
are averaged, 500 IU per day or less was given in six
studies (n=1648), 500799 IU per day in four studies
(n=646), and 800 IU per day or more in 13 studies
(n=1788). Three studies had three groups (two dierent
Figure 2: Funnel plots of femoral neck (A) and total hip (B) bone mineral density data, testing for
publication bias
Evidence of positive bias (assessed with Eggers test) was apparent for both, but not at the other bone mineral
density measurement sites (data not shown).
20
15
10
05
00
S
t
a
n
d
a
r
d

e
r
r
o
r
A Femoral neck
3 2 1 0 1 2 3 4 4
20
15
10
05
00
S
t
a
n
d
a
r
d

e
r
r
o
r
Dierence in means
B Total hip
Eggers test p=002
Eggers test p=0005
Articles
www.thelancet.com Vol 383 January 11, 2014 151
vitamin D doses and a control group).
32,33,35
In one of these
studies,
32
the results were reported separately for men
and women. For this study, we pooled the results for men
and women, and for all three studies, the results from
the two vitamin D groups were pooled and compared
with the control group.
Follow-up concentrations of 25-hydroxyvitamin D were
reported in 19 studies; in all cases, concentrations were
signicantly increased in individuals on treatment
(table 1). The unweighted mean across all studies
increased from 53 nmol/L to 92 nmol/L.
Bone mineral density was measured at one to ve sites
(lumbar spine, femoral neck, total hip, trochanter, total
body, or forearm) in each study (gure 1). The total hip
site was assessed in 12 studies and the trochanter in
three.
21,27,34
Because the trochanter is the major component
of the total hip, we have analysed these data together.
There were six ndings of statistically signicant bene-
cial eects on bone mineral density, four studies
reported benecial eects at one site only,
1921
and one
study
34
reported benecial eects in both femoral regions
(gure 1). Each of these studies assessed other sites and
failed to nd signicant eects. Two studies reported
detrimental eects at the total body (p005).
32,43
In three of the ve studies with positive outcomes,
baseline 25-hydroxyvitamin D concentrations were low
(26, 29, and 36 nmol/L),
21,28,34
but in the other two,
concentrations of 25-hydroxyvitamin D in the control
group were 66 and 71 nmol/L.
19,20
Four studies
23,29,31,32
with
baseline 25-hydroxyvitamin D concentrations of less than
50 nmol/L did not produce positive outcomes, although
in one study, the vitamin D dose was only 195 IU per day
and in another, 1 g calcium was given to both groups
every day.
31
Three of the positive studies used vitamin D
doses of 400 IU per day,
19,21,34
one compared 700 IU per day
with 100 IU per day,
20
and one provided 300 000 IU per
year (820 IU per day) by injection.
28
Three positive studies
were of 12 months duration, and two lasted 24 months.
All positive studies were in women, four in older white
women
1921,28
and one in Bangladeshi women.
34
Thus, no
suggestion of ethnic dierences in response was evident.
Studies comparing higher vitamin D doses with 800 IU
per day
36,37
showed no dierences.
Figure 1 shows the results of the meta-analysis. Two
studies from table 1 were not included in this analysis. In
the Venkatachalam study
26
there was a 9-year age
dierence between the two treatment groups (49 years vs
58 years), suggesting that dierences in bone loss might
not only be related to treatment allocation. The bone
mineral density changes tended to be more positive in the
placebo group in this study, but this nding was not
signicant (data not shown). The Viljakainen study
33
was
excluded because no quantitative data in the original
publication were available, and we have been unable to
obtain them from the authors. Investigators of the original
publication reported no eects on bone mineral density.
We reported no signicant eect of vitamin D on bone
mineral density in either the spine or total hip. By
contrast, we noted a signicant increase in femoral neck
bone mineral density, but evidence of heterogeneity in
the data (gure 1). Meta-regression exploring the eects
of age, study duration, number of participants, sex,
25-hydroxyvitamin D concentration, weight, vitamin D
dose, baseline bone mineral density, and type of DXA
machine on the femoral neck bone mineral density
treatment eect did not show any signicant interactions
(data not shown). In the forearm and total body scans,
both predominantly assessing cortical bone, net changes
were negative, although neither was signicant (gure 1).
We recorded evidence of bias towards positive results at
both hip sites, which might have contributed to the
positive femoral neck results. However, an analysis
restricted to the studies that reported both spine and
femoral neck showed the change in bone mineral density
to be greater at the femoral neck (p=0012; data not
shown). A similar comparison in studies reporting both
25OHD concentrations Dose Duration Calcium
<50 nmol/L 50 nmol/L p
value
<800 800 p
value
12 months >12 months p
value
Calcium No calcium p
value
n %
dierence
n %
dierence
n %
dierence
n %
dierence
n %
dierence
n %
dierence
n %
dierence
n %
dierence
Lumbar
spine
7 01 (03
to 05)
9 00 (03
to 03)
09 7 04 (00
to 08)*
10 01 (04
to 02)
004 8 01 (04
to 06)
9 00 (04
to 03)
06 10 01 (02
to 03)
7 01 (06
to 07)
>09
Total hip 6 06 (01
to 12)
9 00 (02
to 02)
009 2 14 (18
to 45)
13 01 (01
to 03)
04 8 02 (02
to 07)
7 02 (01
to 05)
08 9 00 (02
to 02)
6 07 (01
to 16)
01
Femoral
neck
6 10 (02
to 19)*
6 05 (02
to 13)
02 6 14 (04
to 24)*
7 03 (02
to 08)
006 5 12 (01
to 24)
8 07 (00
to 13)*
05 5 04 (05
to 13)
8 11 (04
to 19)*
02
Forearm 2 03 (07
to 02)
3 04 (12
to 04)
06 1 03 (49
to 43)
5 03 (07
to 01)
>09 6 03 (07
to 01)
4 03 (07
to 01)
2 07 (17
to 04)
05
Total
body
3 07 (19
to 05)
5 00 (02
to 02)
03 3 06 (17
to 06)
5 01 (03
to 01)
04 5 05 (11
to 02)
3 01 (02
to 03)
012 5 00 (01
to 02)
3 09 (21
to 04)
02
For n, several studies in subgroup. p value for heterogeneity between subgroups. 25OHD=25-hydroxyvitamin D. *Changes for which the CIs do not cross zero.
Table 2: Meta-analysis of vitamin D eects on bone mineral density in subgroups of trials
Articles
152 www.thelancet.com Vol 383 January 11, 2014
femoral neck and total hip or trochanter did not nd
those sites to be dierent (p=031; data not shown).
Table 2 summarises eects of bone mineral density in
subgroups of trials categorised according to study
characteristics. These data suggest that benets are more
pronounced in studies using vitamin D doses of less
than 800 IU per day in the lumbar spine, and this
eect was independent of the eects of baseline
25-hydroxyvitamin D (data not shown). Study duration
and administration of calcium to all trial participants did
not aect outcomes. The eect of mean age was analysed
similarly in three categories: individuals younger than
50 years, 5075 years, and 75 years or older. We noted no
evidence of an age eect (p values 01506 for the
various sites; data not shown). Three trials had an open-
label study design,
22,23,28
and two studies
30,36
reported
results for only one bone mineral density site, raising the
possibility of selective reporting. We did a sensitivity
analysis excluding these ve trials at higher risk of bias.
Analyses of the remaining 16 trials produced very similar
results for each bone mineral density site to the overall
results (data not shown), suggesting that trial quality did
not aect outcomes.
Discussion
This systematic review provides very little evidence of an
overall benet of vitamin D supplementation on bone
density. Although small increases in bone density at
some skeletal sites in some studies were reported, when
these increases are oset against the individual ndings
of deleterious eects, the number of positive results is
little better than what would have been expected by
chance. Findings of the meta-analysis are similar; we
reported a small but signicant increase in bone density
in the femoral neck, but not at the closely related total hip
site. Such a localised eect could be artifactual, or could
be a chance nding. The femoral neck has more cortical
bone than does the total hip region and is usually less
responsive to interventions than are trabecular-rich sites,
including to the treatment of osteomalacia.
44
The other
cortical-rich sites (forearm and total body) did not show a
positive eect, so this is not a cortical-specic eect.
Single-site eects on bone mineral density have not been
associated with reduction in fractures in individuals
given other interventions.
Several studies merit individual mention. Results
from the investigation by Tuppurainen and colleagues
22

showed the largest end-of-study increases in femoral
neck bone mineral density. This large dierence between
groups at 5 years is contrary to what was reported at 1 and
2 years, when the vitamin D group had smaller increases
in bone mineral density than did the control group. No
signicant benet was noted from the use of vitamin D
during the whole study. However, exclusion of the
Tuppurainen study
22
from the meta-analysis of bone
mineral density of femoral neck does not change the
results. The only studies to show signicant increases in
bone mineral density in populations not decient in
vitamin D were from the two studies by Dawson-Hughes
and coworkers.
19,20
The reasons for these atypical
responses are not clear, but both studies were undertaken
at dierent times in the same cohort, so they are not
independent studies. This cohort was originally selected
for its low dietary calcium intake (<400 mg per day).
These are very low calcium intakes for a western
population, suggesting that these data should not be
generalised to most western women who need
prophylaxis against postmenopausal osteo porosis. Islam
and colleagues study
34
is notable because of the nding
of clinically signicant increases in bone density at the
total hip and femoral neck. These might be chance
ndings, but this study was done in Bangladeshi women
with mean baseline 25-hydroxyvitamin D con cen trations
of 36 nmol/L, who are likely to have had low dietary
calcium intakes, although these data were not reported.
Why ndings from other studies in populations with
similarly low 25-hydroxyvitamin D concentrations did
not show improvements in bone density is unclear, but
might be accounted for by increased calcium intakes or
by the well recognised inaccuracy of many assays for
25-hydroxyvitamin D
45
ie, the participants in Islam and
coworkers study
34
might have been more decient in
vitamin D than the measurements suggest. The more
recent studies in this review (ie, done in the past 5 years)
used mass spectrometry or the more reliable of the
immunoassays,
43
so should have identied seriously
decient populations.
The negative ndings from this systematic review of
the eects of vitamin D supplementation on bone density
are entirely consistent with those from meta-analyses of
the e cacy of this intervention at reducing the risk of
fracture.
7,8
These ndings sharply conict with those of
other reviews, which show that vitamin D has a sub-
stantial benecial eect on fracture risk.
46,47
These reviews
invariably include studies in which calcium and
vita min D is the intervention assessed. Calcium supple-
ments suppress bone turnover by about 20% and have
benecial eects on bone density,
48
so inclusion of
studies in which calcium is part of the intervention and
attributing the benets to vitamin D is inappropriate.
The eects of the combination of calcium and vitamin D
on fracture risk are indistinguishable from those of
calcium alone,
49
suggesting that vitamin D contribution
is small in most studies. Findings from the study by
Chapuy and coworkers
50
have most clearly shown the
benets of calcium and vitamin D. In this study, the
placebo group had very low 25-hydroxyvitamin D concen-
trations (mean 25 nmol/L, measured in 69 women in the
placebo group at 12 months) and calcium intakes of only
500 mg per day. Intervention produced a dierence
between groups in total hip bone mineral density of
73%, so the 27% reduction in hip fractures was not
surprising. These benets are consistent with the eects
of vitamin D and calcium on bone mineral density in
Articles
www.thelancet.com Vol 383 January 11, 2014 153
individuals who are markedly vitamin D decient
(some possibly osteomalacic). The suggested benet of
vitamin D plus calcium on falls
51
might have contributed
to the positive outcome in the study by Chapuy and
colleagues. The changes in bone mineral density
recorded in our meta-analysis are much smaller than
those associated with fracture preven tion from any
intervention. Thus, the antifracture e cacy noted in the
Chapuy study should not be expected to be reproduced in
substantially less decient populations, or from the use
of vitamin D alone.
The negative ndings of our analysis contrast with the
widely held perception that vitamin D works directly on
bone cells to promote mineralisation.
31,35,52
This perception
is probably incorrect. Although the vitamin D receptor
knockout mouse has reduced bone mass, this phenotype
can be completely corrected and normal mineral isation
restored by the provision of calcium and phosphate
supplements.
42
Findings of studies of selective vitamin D
receptor knockout show that the skeletal phenotype of
the vitamin D receptor knockout mouse can be
reproduced by selective knockout of the receptor in
enterocytes,
53
and that the skeletal abnormalities of the
receptor global knockout mouse can be corrected by
selective replacement of the vitamin D receptor in entero-
cytes.
54,55
Thus, expression of the vitamin D receptor in
enterocytes is both necessary and adequate for normal
bone mineralisation. Selective loss of vitamin D receptor
from bone actually increases bone mass.
53,56
This nding
can be explained by the fact that vitamin D receptor in
bone (in cells of the osteoblast lineage) regulates RANKL
and osteoprotegerin production to stimulate osteo-
clastogenesis.
57
Additionally, vitamin D directly inhibits
mineral isation of bone, through increasing local pyro-
phosphate concentrations.
53
Thus, vitamin D is not a
compound mainly responsible for maintenance of bone
calcium content, but rather for maintenance of circu-
lating calcium concentrations, which are crucial for
cardiac and neuronal function. Bone is merely a reservoir
that can be drawn on for this purpose. Of course, in
states of vitamin D deciency, secondary hyper para-
thyroidism arises, which also stimulates the pro duction
of RANKL and osteoclastogenesis. Thus, the biphasic
eects of vitamin D on bone mass are unsurprising,
because either low or high concentrations can potentially
accelerate bone resorption. Some studies of high-dose
calciferol or 1-hydroxylated vitamin D metabolites show
increased bone loss
58
and fractures,
59,60
which is consistent
with this nding of biphasic eects.
Although our analysis has restrictions common to
individual studies (some were unblinded, were short
term, used low doses of vitamin D, and most partici-
pants had adequate calcium intakes), it also has many
strengths. The total number of participants is large for
assessment of a bone mineral density endpoint, most
individual studies were well powered, with wide ranges of
baseline 25-hydroxyvitamin D concentrations, vita min D
doses, dosing regimens, and ethnic groups. Therefore,
the failure of any one study and of the meta-analysed data
to show consistent benet across the skeleton is likely to
be a real nding.
The clinical implication of our ndings is that the
widespread use of vitamin D supplements for skeletal
protection in adults without specic risk factors for
vitamin D deciency is not justied. This assertion
complies with ndings from previous meta-analyses of
studies of fracture,
7,8
and suggests that no basis exists for
the notion that those studies failed to detect a clinically
signicant benet as a result of deciencies in design or
execution. The small eects of vitamin D supplements
on bone mineral density do not exclude a benecial eect
on fracture by prevention of falls,
51
although ndings
from the meta-analyses of fracture provide no evidence
of this eect.
7,8
Individuals at risk of vitamin D deciency
as a result of skin pigmentation or low sunlight exposure
(eg, a result of veiling or frailty) might indeed benet, so
targeting of the intervention is important if the balance
of risk and benet is to be positive.
Further studies of vitamin D supplements in these
groups are needed to establish associations between
baseline 25-hydroxyvitamin D concentration and responses
to vitamin D supplements. Such analyses might contribute
to an improved denition of vitamin D deciency. In the
past few years, some clinicians have been enthusiastic
about use of vitamin D supplements in doses of more
than 1000 IU per day, with a view to achieve serum
25-hydroxyvitamin D concen trations greater than
75 nmol/L. Our analysis gives no support for this target
concentration of 25-hydroxyvitamin D, because the
existing evidence of benet on bone mineral density
comes from doses of 400800 IU per day. In fact, data from
studies
36,37
comparing high-dose with low-dose vitamin D
supple ments suggest that individuals on a low dose have
improved bone mineral density, although dierences
between the groups were not signicant. Although these
conclusions contrast with those of many advocates in the
specialty, they align well with the 2010 report from the
Institute of Medicine,
5
which concluded (partly on the
basis of histological evidence) that 40 nmol/L was an
adequate concentration of serum 25-hydroxyvitamin D,
and that most adults in North America do not need
supplementation. The increasing practice for measure-
ment and supple mentation of vitamin D is expensive.
61

Our data suggest that the targeting of low-dose vitamin D
supplements only to individuals who are likely to be
decient could free up substantial resources that could be
better used elsewhere in health care.
Contributors
All authors developed the concept of this study. IRR and MJB wrote the
protocol. IRR and MJB collated the data for the study and MJB did the
statistical analyses. The rst draft of the manuscript was written by IRR
and thoroughly revised by MJB and AG.
Conicts of interest
We declare that we have no conicts of interest.
Articles
154 www.thelancet.com Vol 383 January 11, 2014
Acknowledgments
This study was funded by the Health Research Council of New Zealand.
We thank Greg Gamble for assistance with the meta-regression analyses.
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